Eculizumab is an orphan drug with indications for extremely rare autoimmune disorders. It is primarily prescribed for use in patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome; but is also highly effective in the treatment of myasthenia gravis, among others. By binding to the C5 protein in the complement system, eculizumab effectively inhibits cellular hemolysis and autoimmune reactions. Despite this effective treatment, some patients reported no improvement in symptoms. Genetic sequencing revealed three distinct C5 mutations in the non-responders and these polymorphisms appeared to be most prevalent among Japanese, Korean and African populations. Here, we present an overview of the current and potential future applications of eculizumab, as well as the disadvantages of eculizumab treatment in patients with C5 polymorphisms.

Atypical haemolytic uremic syndrome (aHUS) is a rare disorder characterised by complement-mediated thrombotic microangiopathy (TMA). Despite clinical guidelines, the diagnosis and treatment of aHUS in its early stages remains challenging. This study examined the annual trends in aHUS clinical practices in Japan and explored factors influencing early diagnosis and treatment. Using data from the 2011-2020 Diagnosis Procedure Combination database, 3096 cases with the HUS disease code were identified, of which 217 were confirmed as aHUS and treated with eculizumab or plasma exchange. Early initiation, defined as starting eculizumab or plasma exchange within 7 days of admission, was the focus of the study. Our study revealed no significant changes over time in the number of aHUS diagnoses, cases treated with eculizumab, or early initiation cases. Early initiation cases underwent haemodialysis earlier and had ADAMTS13 activity measured earlier, shorter hospital stays, and lower hospitalisation costs than late initiation cases. In conclusion, we found no increase in the number of newly diagnosed aHUS cases or early treatment initiation over time. Early recognition of TMA and differentiation of the causative disease are crucial for identifying potential aHUS cases, which may lead to better patient prognoses.

BACKGROUND: The spectrum of diseases characterized by the development of renal thrombotic microangiopathy (TMA) encompasses the malignant hypertension (MHT). TMA in MHT has conventionally been regarded as a variation of secondary TMA, the treatment of which is restricted to the stabilization of blood pressure levels, a measure that frequently fails to prevent the rapid progression to end-stage renal disease in patients. Nevertheless, there exists a rationale to suggest that, in certain instances, endothelial damage in MHT might be rooted in the dysregulation of the complement system (CS), thereby presenting potential opportunities for the implementation of complement-blocking therapy.
OBJECTIVE: To study clinical manifestations and genetic profile of CS in patients with morphologically confirmed renal TMA combined with severe AH.
METHODS: 28 patients with morphologically verified renal TMA and severe AH were enrolled to the study. Patients with signs of microangiopathic hemolysis and thrombocytopenia were not included in the study due to possible compliance with the criteria for atypical hemolytic uremic syndrome (aHUS). The prevalence of rare genetic defects (GD) of the CS was assessed by molecular genetic analysis (search for mutations in the clinically significant part of the human genome - exome) by next-generation sequencing technology (NGS).
RESULTS: GD of CS were detected in a quarter of patients. Rare genetic variants classified as \"likely pathogenic\" including defects in CFI, C3, CD46, CFHR4, CFHR5 genes were detected in five cases. Two patients were found to have chromosomal deletions containing CFH-related proteins genes (CFHR1, CFHR3).
CONCLUSIONS: Rare variants of CS genes linked to aHUS were found in 25% of patients with renal TMA, the genesis of which was originally thought to be secondary and attributed to MHT, with partial or complete absence of hematological manifestations of microangiopathic pathology. The key to confirming TMA associated with MHT, particularly in the absence of microangiopathic hemolysis and thrombocytopenia, elucidating its nature, and potentially effective complement-blocking therapy in patients with GD of CS, appears to be a genetic study of CS combined with a morphological study of a renal biopsy.
Обоснование. Круг заболеваний, характеризующихся развитием почечной тромботической микроангиопатии (ТМА), включает в себя злокачественную артериальную гипертонию (ЗАГ). ТМА при ЗАГ традиционно рассматривается как вариант вторичной ТМА, симптоматическая терапия которой сводится лишь к стабилизации уровня артериального давления, что нередко не позволяет избежать быстрого развития у пациентов терминальной стадии почечной недостаточности. Однако есть основания предполагать, что в ряде случаев в основе эндотелиального повреждения при ЗАГ лежит дисрегуляция системы комплемента (СК), что открывает перспективы для применения комплемент-блокирующей терапии. Цель. Изучить клинические проявления и генетический профиль СК у пациентов с морфологически подтвержденной почечной ТМА, сочетающейся с тяжелыми формами АГ. Материалы и методы. В исследование включены 28 пациентов с морфологически верифицированной почечной ТМА и тяжелыми формами АГ. Больных, имевших признаки микроангиопатической гемолитической анемии и тромбоцитопении, не включали ввиду возможного соответствия критериям атипичного гемолитико-уремического синдрома. Общеклинические данные и распространенность редких генетических дефектов (ГД) СК оценивали путем проведения молекулярно-генетического анализа (поиска мутаций в клинически значимой части генома человека – экзоме) методом высокопроизводительного секвенирования (NGS). Результаты. ГД СК выявлены у 1/4 больных. В 5 случаях обнаружены редкие генетические варианты, классифицированные как «вероятно патогенные», включавшие дефекты генов CFI, C3, CD46, CFHR4, CFHR5. У 2 пациентов выявлены хромосомные делеции, содержащие гены релейт-факторов CFH (CFHR1, CFHR3). Заключение. У 25% больных с почечной ТМА, генез которой первоначально расценен как вторичный и атрибутирован к ЗАГ, при частичном или полном отсутствии гематологических проявлений микроангиопатической патологии обнаружены редкие варианты генов СК, ассоциированные с атипичным гемолитико-уремическим синдромом. Генетическое исследование СК в сочетании с морфологическим исследованием почечного биоптата являются, по-видимому, ключевыми инструментами для верификации ТМА, ассоциированной с ЗАГ, особенно в отсутствие микроангиопатической гемолитической анемии и тромбоцитопении, уточнения ее природы и применения потенциально эффективной комплемент-блокирующей терапии у пациентов с ГД СК.

UNASSIGNED: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS.
UNASSIGNED: This analysis reports 2-year data from 2 phase 3, single-arm studies.
UNASSIGNED: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219).
UNASSIGNED: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight.
UNASSIGNED: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart.
UNASSIGNED: All analyses used descriptive statistics. No formal statistical comparisons were performed.
UNASSIGNED: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m2) and pediatric patients (82.5 mL/min/1.73 m2). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years.
UNASSIGNED: Limitations were the small sample of pediatric switch patients and limited availability of genetic data.
UNASSIGNED: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.
This research tested a drug called ravulizumab for the treatment of atypical hemolytic uremic syndrome (aHUS). aHUS is a rare disease that causes clots in tiny blood vessels. This can damage the kidneys and other organs. We analyzed data from 2 clinical trials in which children and adults with aHUS received ravulizumab through a tube placed in a vein (intravenous line). They received ravulizumab every 4-8 weeks depending on their weight. We found that treating patients for 2 years with ravulizumab was associated with improved blood health, kidney function, and quality of life and was well tolerated. These results support ravulizumab as a long-term treatment for people with aHUS.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy. Genetic defects in the alternative complement (AP) pathway have been identified in 60-70% of individuals. Eculizumab is recommended as a first-line therapy.
METHODS: We collected the clinical data of a pediatric patient with aHUS accompanied by protein-losing enteropathy (PLE). Genetic testing was performed. Related literature on aHUS combined with PLE was reviewed.
RESULTS: A 15-year-old Chinese girl was diagnosed with aHUS at 3.7 years of age and experienced five episodes; her symptoms completely resolved with plasma treatment. Severe gastrointestinal symptoms and hypoalbuminemia presented after the first episode, and PLE was diagnosed. A novel homozygous CD46 variant was identified, and FACS revealed significantly decreased CD46 expression. She presented at a recent relapse with persistent GI symptoms and headache and progressed to chronic kidney failure; peritoneal dialysis was initiated. Eculizumab was given 8 months after the last recurrence. Surprisingly, PLE was cured. Afterward, dialysis was discontinued, and eGFR recovered to 44.8 ml/min/1.73 m2. A review of the literature indicated that PLE with thrombosis was caused by CD55 variants via hyperactivation of the AP system. We report an aHUS patient with PLE caused by CD46 variants. Symptoms of both PLE and aHUS were significantly alleviated in our patient and patients with CD55 variants treated with eculizumab, indicating that PLE was a new symptom of aHUS in our patient with a CD46 variant.
CONCLUSIONS: Our case expands the phenotype of aHUS caused by a CD46 mutation and provides evidence of the efficacy of eculizumab after a long phase of chronic kidney failure.

UNASSIGNED: Atypical hemolytic uremic syndrome (aHUS) poses a significant health challenge due to its rarity and severity within the spectrum of thrombotic microangiopathy. Despite efforts to optimize and personalize health care for patients with aHUS, understanding the individual experiences, needs, and desires of patients with aHUS and their relatives remains limited.
UNASSIGNED: Here, we present a nationwide, exploratory, qualitative interview study with a direct content analysis approach. In-depth interviews and a 6-week evaluation were audio-recorded and conducted using a semistructured topic guide, based on the Institute for Positive Health (IPH) model.
UNASSIGNED: Analysis of 10 interviews involving 6 patients with aHUS and 13 relatives revealed the prevalence of long-term disease symptoms in adult patients, notably fatigue, which significantly impacted daily functioning. Moreover, the resilience demonstrated by patients and their relatives was noteworthy; however, the acute phase of aHUS and the unpredictable nature of disease recurrence could profoundly affect mental well-being. The emotional toll of aHUS is pervasive, with feelings of fear, guilt, and trauma persisting across disease phases in both patients and relatives. Challenges in medical care, including delays in diagnosis and the need for personalized and uniform protocols, were highlighted. Support was deemed crucial, indicating the necessity for enhancements in the accessibility to comprehensible disease information and psychological counseling. Finally, complexities surrounding genetic testing and carriership were discussed.
UNASSIGNED: This study underscores the profound, enduring, and multifaced impact of aHUS. The insights gleaned from the experiences and needs of patients with aHUS and their relatives could lay the foundation for development and implementation of more personalized innovations in aHUS health care.

BACKGROUND: No reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies.
METHODS: A 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening.
CONCLUSIONS: This is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment.

BACKGROUND: The emergence of new SARS-CoV-2 variants and the global COVID-19 pandemic spurred urgent vaccine development. While common vaccine side effects are well-documented, rare adverse events necessitate post-marketing surveillance. Recent research linked messenger RNA vaccines to thrombotic microangiopathy (TMA), a group of syndromes characterized by microvascular hemolytic anemia and thrombocytopenia. This report describes a new-onset atypical hemolytic-uremic syndrome (aHUS) occurring after COVID-19 vaccination and complements recent literature.
METHODS: A previously healthy 25-year-old woman developed malaise, nausea, edema, and renal dysfunction 60 days postvaccination. Laboratory findings confirmed TMA diagnosis. Genetic testing for complement system mutations was negative. Kidney biopsy supported the diagnosis, and the patient required hemodialysis.
CONCLUSIONS: This case illustrates the rare occurrence of aHUS following COVID-19 vaccination, with unique characteristics compared to previous reports. Despite the critical role of vaccination in pandemic control, emerging adverse events, such as vaccine-related TMA, must be recognized and investigated. Additional clinical trials are imperative to comprehend the clinical features and pathophysiological mechanisms underlying TMA associated with COVID-19 vaccination.

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

The complement and coagulation systems are ancestrally related mechanisms of serine protease-induced protein activation. Recent studies have shown that the complement system enhances platelet aggregation by activating platelets and vascular endothelial cells. This system is also involved in the expression of tissue factor, which induces the coagulation reaction. Activated platelets and coagulation factors are also known to activate the complement system. In diseases involving the complement system, such as paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, and atypical hemolytic uremic syndrome, excessive activation of this system contributes to complement-mediated thrombosis. The anti-C5 antibody eculizumab has shown a remarkable thromboprophylactic effect in these complement diseases. The recent surge in development of new anti-complement agents has raised expectations for the advancement of treatments and preventive measures for thrombosis associated with complement disorders. This review outlines the crosstalk between these two systems, and describes the mechanisms of several diseases featuring both thrombosis and complement activation.